{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T09:29:21Z","timestamp":1791278961113,"version":"4.1.0"},"reference-count":53,"publisher":"American Chemical Society (ACS)","issue":"49","license":[{"start":{"date-parts":[[2015,11,18]],"date-time":"2015-11-18T00:00:00Z","timestamp":1447804800000},"content-version":"vor","delay-in-days":365,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_termsofuse.html"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["CA106150"],"award-info":[{"award-number":["CA106150"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,12,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Lactimidomycin (LTM, 1) and iso-migrastatin (iso-MGS, 2) belong to the glutarimide-containing polyketide family of natural products. We previously cloned and characterized the mgs biosynthetic gene cluster from Streptomyces platensis NRRL 18993. The iso-MGS biosynthetic machinery featured an acyltransferase (AT)-less type I polyketide synthase (PKS) and three tailoring enzymes (MgsIJK). We now report cloning and characterization of the ltm biosynthetic gene cluster from Streptomyces amphibiosporus ATCC 53964, which consists of nine genes that encode an AT-less type I PKS (LtmBCDEFGHL) and one tailoring enzyme (LtmK). Inactivation of ltmE or ltmH afforded the mutant strain SB15001 or SB15002, respectively, that abolished the production of 1, as well as the three cometabolites 8,9-dihydro-LTM (14), 8,9-dihydro-8S-hydroxy-LTM (15), and 8,9-dihydro-9R-hydroxy-LTM (13). Inactivation of ltmK yielded the mutant strain SB15003 that abolished the production of 1, 13, and 15 but led to the accumulation of 14. Complementation of the \u0394ltmK mutation in SB15003 by expressing ltmK in trans restored the production of 1, as well as that of 13 and 15. These results support the model for 1 biosynthesis, featuring an AT-less type I PKS that synthesizes 14 as the nascent polyketide intermediate and a cytochrome P450 desaturase that converts 14 to 1, with 13 and 15 as minor cometabolites. Comparative analysis of the LTM and iso-MGS AT-less type I PKSs revealed several unusual features that deviate from those of the collinear type I PKS model. Exploitation of the tailoring enzymes for 1 and 2 biosynthesis afforded two analogues, 8,9-dihydro-8R-hydroxy-LTM (16) and 8,9-dihydro-8R-methoxy-LTM (17), that provided new insights into the structure\u2013activity relationship of 1 and 2. While 12-membered macrolides, featuring a combination of a hydroxyl group at C-17 and a double bond at C-8 and C-9 as found in 1, exhibit the most potent activity, analogues with a single hydroxyl or methoxy group at C-8 or C-9 retain most of the activity whereas analogues with double substitutions at C-8 and C-9 lose significant activity.<\/jats:p>","DOI":"10.1021\/bi501396v","type":"journal-article","created":{"date-parts":[[2014,11,18]],"date-time":"2014-11-18T09:52:42Z","timestamp":1416304362000},"page":"7854-7865","source":"Crossref","is-referenced-by-count":24,"title":["Comparative Characterization of the Lactimidomycin\nand iso-Migrastatin Biosynthetic Machineries Revealing Unusual Features\nfor Acyltransferase-less Type I Polyketide Synthases and Providing\nan Opportunity To Engineer New Analogues"],"prefix":"10.1021","volume":"53","author":[{"given":"Jeong-Woo","family":"Seo","sequence":"first","affiliation":[{"name":"University of Wisconsin\u2500Madison , , , ,","place":["Madison, Wisconsin, United States, 53705"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Ma","sequence":"additional","affiliation":[{"name":"The Scripps Research Institute , , , , ,","place":["Jupiter, Florida, United States, 33458"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Kwong","sequence":"additional","affiliation":[{"name":"The Scripps Research Institute , , , , ,","place":["Jupiter, Florida, United States, 33458"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhua","family":"Ju","sequence":"additional","affiliation":[{"name":"University of Wisconsin\u2500Madison , , , ,","place":["Madison, Wisconsin, United States, 53705"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Si-Kyu","family":"Lim","sequence":"additional","affiliation":[{"name":"University of Wisconsin\u2500Madison , , , ,","place":["Madison, Wisconsin, United States, 53705"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Jiang","sequence":"additional","affiliation":[{"name":"University of Wisconsin\u2500Madison , , , ,","place":["Madison, Wisconsin, United States, 53705"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy R.","family":"Lohman","sequence":"additional","affiliation":[{"name":"The Scripps Research Institute , , , , ,","place":["Jupiter, Florida, United States, 33458"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunying","family":"Yang","sequence":"additional","affiliation":[{"name":"The Scripps Research Institute , , , , ,","place":["Jupiter, Florida, United States, 33458"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Cleveland","sequence":"additional","affiliation":[{"name":"The Scripps Research Institute , , , , ,","place":["Jupiter, Florida, United States, 33458"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuel","family":"Zazopoulos","sequence":"additional","affiliation":[{"name":"Thallion Pharmaceuticals, Inc. , , ,","place":["Montreal, Quebec, Canada, H4S 2C8"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris M.","family":"Farnet","sequence":"additional","affiliation":[{"name":"Thallion Pharmaceuticals, Inc. , , ,","place":["Montreal, Quebec, Canada, H4S 2C8"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben","family":"Shen","sequence":"additional","affiliation":[{"name":"University of Wisconsin\u2500Madison , , , ,","place":["Madison, Wisconsin, United States, 53705"]},{"name":"The Scripps Research Institute , , , , ,","place":["Jupiter, Florida, United States, 33458"]},{"name":"The Scripps Research Institute , , , , ,","place":["Jupiter, Florida, United States, 33458"]},{"name":"The Scripps Research Institute , , , , ,","place":["Jupiter, Florida, United States, 33458"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2014,11,18]]},"reference":[{"key":"2026090202134978800_cit1","doi-asserted-by":"crossref","first-page":"11930","DOI":"10.1021\/ja053118u","article-title":"Iso-migrastatin\ncongeners from Streptomyces platensis and generation\nof a glutarimide polyketide library featuring the dorrigocin, lactimidomycin,\nmigrastatin, and NK30424 scaffolds","volume":"127","author":"Ju","year":"2005","journal-title":"J. Am. Chem.\nSoc."},{"key":"2026090202134978800_cit2","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.1002\/cbic.201000370","article-title":"Multifaceted modes\nof action for the glutarimide-containing polyketides\nrevealed","volume":"11","author":"Rajski","year":"2010","journal-title":"ChemBioChem"},{"key":"2026090202134978800_cit3","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.7164\/antibiotics.45.1433","article-title":"Lactimidomycin, a new glutarimide\ngroup antibiotic. Production, isolation,\nstructure and biological activity","volume":"45","author":"Sugawara","year":"1992","journal-title":"J. Antibiot."},{"key":"2026090202134978800_cit4","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.7164\/antibiotics.53.1130","article-title":"Migrastatin, a new inhibitor of tumor\ncell migration from Streptomyces sp. MK929-43F1.\nTaxonomy, fermentation, isolation and biological activities","volume":"53","author":"Nakae","year":"2000","journal-title":"J. Antibiot."},{"key":"2026090202134978800_cit5","doi-asserted-by":"crossref","first-page":"442","DOI":"10.7164\/antibiotics.55.442","article-title":"Absolute configuration\nof migrastatin, a novel 14-membered ring macrolide","volume":"55","author":"Nakamura","year":"2002","journal-title":"J. Antibiot."},{"key":"2026090202134978800_cit6","doi-asserted-by":"crossref","first-page":"870","DOI":"10.7164\/antibiotics.47.870","article-title":"Dorrigocins: Novel\nantifungal antibiotics that change the morphology of ras-transformed\nNIH\/3T3 cells to that of normal cells. II. Isolation and elucidation\nof structures","volume":"47","author":"Hochlowski","year":"1994","journal-title":"J. Antibiot."},{"key":"2026090202134978800_cit7","doi-asserted-by":"crossref","first-page":"875","DOI":"10.7164\/antibiotics.47.875","article-title":"Dorrigocins: Novel antifungal antibiotics\nthat change\nthe morphology of ras-transformed NIH\/3T3 cells to that of normal\ncells. III. Biological properties and mechanism of action","volume":"47","author":"Kadam","year":"1994","journal-title":"J. Antibiot."},{"key":"2026090202134978800_cit8","doi-asserted-by":"crossref","first-page":"141","DOI":"10.7164\/antibiotics.55.141","article-title":"Migrastatin and a new\ncompound, isomigrastatin, from Streptomyces platensis","volume":"55","author":"Woo","year":"2002","journal-title":"J. Antibiot."},{"key":"2026090202134978800_cit9","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.7164\/antibiotics.54.1111","article-title":"NK30424A and B, novel\ninhibitors of lipopolysaccharide-induced tumour necrosis factor \u03b1\nproduction, produced by Streptomyces sp. NA30424","volume":"54","author":"Takayasu","year":"2001","journal-title":"J. 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U.S.A."},{"key":"2026090202134978800_cit18","doi-asserted-by":"crossref","first-page":"5183","DOI":"10.1021\/ol702249g","article-title":"New lactimidomycin\ncongeners shed insight into lactimidomycin biosynthesis in Streptomyces amphibiosporus","volume":"9","author":"Ju","year":"2007","journal-title":"Org.\nLett."},{"key":"2026090202134978800_cit19","doi-asserted-by":"crossref","first-page":"5951","DOI":"10.1016\/j.bmcl.2008.07.072","article-title":"Evaluation\nof new migrastatin and\ndorrigocin congeners unveils cell migration inhibitors with dramatically\nimproved potency","volume":"18","author":"Ju","year":"2008","journal-title":"Bioorg. Med. Chem. 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Toxicol."}],"container-title":["Biochemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/bi501396v","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/bichaw\/article-pdf\/53\/49\/7854\/7904616\/bi501396v.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/bichaw\/article-pdf\/53\/49\/7854\/7904616\/bi501396v.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T06:14:00Z","timestamp":1788329640000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/bichaw\/article\/53\/49\/7854\/775328\/Comparative-Characterization-of-the-Lactimidomycin"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,11,18]]},"references-count":53,"journal-issue":{"issue":"49","published-online":{"date-parts":[[2014,11,18]]},"published-print":{"date-parts":[[2014,12,16]]}},"URL":"https:\/\/doi.org\/10.1021\/bi501396v","relation":{},"ISSN":["0006-2960","1520-4995"],"issn-type":[{"value":"0006-2960","type":"print"},{"value":"1520-4995","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,11,18]]}}}